3-122275959-G-C

Variant names:

• chr3-122275959-G-C
• NM_000388.4:c.1525G>C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000388.4(CASR):​c.1525G>C​(p.Gly509Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.88

Genes affected

CASR (HGNC:1514): (calcium sensing receptor) The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_000388.4 (CASR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to epilepsy, autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, epilepsy, idiopathic generalized, susceptibility to, 8, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 3-122275959-G-C is Pathogenic according to our data. Variant chr3-122275959-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.1525G>C	p.Gly509Arg	missense_variant	Exon 5 of 7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1525G>C	p.Gly509Arg	missense_variant	Exon 5 of 7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.1525G>C	p.Gly509Arg	missense_variant	Exon 5 of 7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.1525G>C	p.Gly509Arg	missense_variant	Exon 5 of 7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.1378-6154G>C		intron_variant	Intron 3 of 4	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 509 of the CASR protein (p.Gly509Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypocalciuric hypercalcemia and/or neonatal severe hyperparathyroidism (PMID: 17698911, 24763815, 31672324, 32638038). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1066880). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Pathogenic:1

Jun 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 13, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM2, PS1 -

Familial hypocalciuric hypercalcemia Pathogenic:1

Jun 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASR c.1525G>C (p.Gly509Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes. To our knowledge, no occurrence of c.1525G>C in individuals affected with Familial Hypocalciuric Hypercalcemia has been reported. A different variant resulting in the same amino acid consequence has been classified as pathogenic by our lab (c.1525G>A), supporting the pathogenicity of this variant. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Mullin_2022). The following publication has been ascertained in the context of this evaluation (PMID: 35356007). ClinVar contains an entry for this variant (Variation ID: 1066880). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.6	H;H;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.3	.;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;.;D
Sift4G	Pathogenic	0.0010	.;.;D
Polyphen		1.0	D;D;.
Vest4		1.0
MutPred		0.78		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-121994806;